Nitro-benzamides useful as anti-arrhythmic agents

ABSTRACT

A compound of formula (I): or a salt thereof, or a solvate thereof, wherein Ar represents substituted or unsubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms any two substituents together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are oxygen or nitrogen; A represents a C 1-4  n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C 1-6  alkyl groups; R 1  represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of of the group of R 2 , R 3  and R 4  represents nitro the remaining members of the group of R 2 , R 3  and R 4  represent hydrogen; X represents a —CO—NH— moiety; and Z represents C 2-4  n-alkylene group wherein each carbon is optionally substituted 1 or 2 C 1-6  alkyl groups; a process for preparing such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in medicine.

This is a continuation of application Ser. No.: 09/825,187 filed Apr. 2,2001, now abandoned, which is a continuation of 09/384,600 filed Aug.27, 1999 now abandoned, which is a divisional of application Ser. No.08/836,019 filed Apr. 25, 1997, now U.S. Pat. No. 54,771,793 which is a371 of International Application No. PCT/EP95/04203 filed Oct. 24, 1995,which claims priority to 94/12806 filed Oct. 26, 1994.

The invention relates to certain novel compounds, to pharmaceuticalcompositions containing such compounds, to a process for the preparationof such compounds and to the use of such compounds as active therapeuticagents.

Anti-arrhythmic agents are classified according to theirelectrophysiological effects on the cardiac cell Vaugham-Williams, 1970,1989): class I agents block the fast sodium current, class II agents arebeta-adrenergic blockers, class III agents block potassium currents,class IV agents block the calcium current, and class V agents arespecific sinus node inhibitors.

A majority of ventricular and atrial arrhythmias are related toreentrant circuit. The prolongation of myocardial refractoriness withinor surrounding such a reentrant circuit is a potential mechanism for themanagement of cardiac arrhythmias.

Because class III antiarrhytmic agents block cardiac potassium currents,they prolong the repolarisation process and increase refractoriness.Consequently class III agents represent the most specific class to treatreentrant arrhythmias.

However, due to their mechanism of action, i.e. a concentrationdependent increase in the cardiac action potential duration, higherdoses of class III antiarrhythmic agents may trigger arrhythmias. Sucharrhythmias, called Torsade de Pointe represent the main adverse effectfor all pure class III compounds currently in development.

European Patent Application, Publication Number 0 245 997 disclosescertain aminoethylsulphoanilides which are stated to have pure class IIIantiarrhythmic properties.

It has now been discovered that certain novel substituted4-nitrobenzamide derivatives induce a self-limiting increase of thecardiac action potential duration, related to a dual blockade of cardiacpotassium and calcium channels. Consequently, they are considered to beuseful anti-arrhythmic agents having an improved pharmacological profileover pure class III anti-arrhythmic agents, in particular they areconsidered to show a low proarrhythmic potential and readily restore thecontractile function of the ischaemic myocardium. They are considered tobe particularly useful for the treatment of atrial or ventricularcardiac arrhythmias.

Accordingly, the invention relates to a compound of formula (I):

or a salt thereof, or a solvate thereof, wherein

Ar represents substituted or unsubstituted aryl, wherein the optionalsubstituents are selected from alkyl, hydroxy or alkoxy or, if attachedto adjacent carbon atoms any two substituents together with the carbonatoms to which they are attached may form a fused heterocyclic ring offive to six atoms wherein one, two or three of the said atoms are oxygenor nitrogen;

A represents a C₁₋₄ n-alkylene group wherein each carbon is optionallysubstituted by 1 or 2 C₁₋₆ alkyl groups;

R₁ represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of thegroup of R₂, R₃ and R₄ represents nitro the remaining members of thegroup of R₂, R₃ and R₄ represent hydrogen;

X represents a —CO—NH— moiety; and

Z represents C₂₋₄ n-alkylene group wherein each carbon is optionallysubstituted by 1 or 2 C₁₋₆ alkyl groups.

Suitable substituents for Ar are 1, or favourably, 2 alkoxy groups,especially methoxy groups, the substituents favourably being attached atthe 3- and 4-positions relative to the point of attachment of Ar tovariable A.

Preferably, Ar represents 3,4-dimethoxyphenyl

Suitably, A represents an unsubstituted C₁₋₄ n-alkylene group.

Preferably, A represents —CH₂—CH₂.

When R₁ is alkyl it is preferably C₂₋₆ alkyl such as C₂₋ alkyl, C₃alkyl, C₄ alkyl, C₅ alkyl or C₆ alkyl.

In one aspect, R₁ is alkylene or cycloalkyl.

Preferably, R₁ is hydrogen.

Suitably, any one of R₂, R₃ and R₄ represents nitro and the remainingmembers of the group of R₂, R₃ and R₄ represent hydrogen.

Preferably, R₂ represents 4-nitro.

Preferably, R₃ and R₄ each represents hydrogen.

Suitably, Z represents an unsubstituted C₂₋₄ n-alkylene group.

Suitably, Z represents CH₂CH₂CH₂.

A particularly preferred compound of formula is N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide or a saltthereof, such as a hydrochloride salt, or a solvate thereof.

As used herein unless otherewise stated, the term “alkyl” includesstraight or branched chain alkyl groups having from 1 to 12, favourably1 to 6 carbon atoms and shall include such alkyl groups when formingpart of other groups such as alkoxy or arylalkyl groups.

As used herein, the term “alkylene” includes straight or branched chainalkylene groups having from 2 to 12, favourably 2 to 6 carbon atoms.

As used herein, the term “cycloalkyl” includes C₃₋₈ cycloalkyl groups,favourably C₅₋₆ carbon groups.

As used herein, unless otherwise stated, the term “aryl” includes phenyland naphthyl, preferably phenyl.

As used herein, unless otherwise stated, “halogen” includes fluorine,chlorine or bromine.

As used herein, the term “cardiac arrhythmia” relates to any variationfrom the normal rhythm of heart beat, including, without limitation,sinus arrhythmia, premature heartbeat, heartblock, fibrillation,flutter, tachycardia, paroxysmal tachycardia and premature ventricularcontractions.

The compounds of formula (I) may possess a chiral carbon atom (forexample when Z represents a branched alkylene group and may thereforeexist in more than one stereoisomeric form. The invention extends to anyof the stereoisomeric forms, including enantiomers of the compounds offormula (I) and to mixtures thereof, including racemates. The differentstereoisomeric forms may be separated or resolved one from the other byconventional methods or any given isomer may be obtained by conventionalstereospecific or asymmetric syntheses.

The pharmaceutically acceptable salts of the compounds of formula (I)include acid addition salts with pharmaceutically acceptable mineralacids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuricand pharmaceutically acceptable organic acids such as acetic, tartaric,maleic, citric, succinic, benzoic, ascorbic, methanesulphonic,α-keto-glutaric, α-glycerophosphoric, and glucose-1-phosphoric acids.Preferably the acid addition salt is a hydrochloride.

Pharmaceutically acceptable salts include pharmaceutically acceptableN-oxides, and the invention extends to these.

The compounds of the formula (I) and their salts may also form solvates,especially pharmaceutically acceptable solvates, such as hydrates, andthe invention extends to these, and especially to the pharmaceuticallyacceptable solvates.

The salts and/or solvates of the compounds of the formula (I) which arenot pharmaceutically acceptable may be useful as intermediates in thepreparation of pharmaceutically acceptable salts of compounds of formula(I) or the compounds of the formula (I) themselves, and as such form anaspect of the present invention.

A compound of formula (I), or a salt thereof, or a solvate thereof, maybe prepared by reacting a compound of formula (II):

wherein A, Ar, R₁ and Z are as defined in relation to formula (I), witha compound of formula (III):

wherein R₂, R₃ and R4 are as defined in relation to formula (I) and L₁represents a leaving group; and thereafter, if required, carrying outone or more of the following optional steps:

(i) converting a compound of formula (I) into a further compound offormula (I);

(ii) preparing a salt of the compound of formula (I) and/or apharmaceutically acceptable solvate thereof.

Compounds of formula (III) are known, commercially available compounds.

The reaction between the compounds of formulae (II) and (III) may becarried out in any suitable inert solvent, such as dichloromethane, inthe presence of a base, usually an organic base, for exampletriethylamine, at a temperature which provides a suitable rate offormation of the required product, generally at a low to ambienttemperature, preferably ambient

A preferred leaving group L₁ is a halogen atom, such as a chlorine atom.

The compounds of formula (II) are known compounds and may be prepared bythe method described in Offenlegungsschrift 2345423.

The compounds of formula (II) may also be prepared by reducing acompound of formula (IV):

wherein A, Ar and R₁ arm as defined in relation to the compound offormula (I) and Z₁ represents C₁₋₃ n-alkylene group wherein each carbonis optionally substituted by a C₁₋₆ alkyl group.

The reduction of the compounds of formulae (IV) may be carried out usingconventional reducing agents and conditions, for example by using ametal hydride reducing agent, such as lithium aluminium hydride, in anaprotic solvent, such as tetrahydrofuran or diethyl ether or mixturesthereof, at a temperature which provides a suitable rate of formation ofthe required product, generally at an elevated temperature andconveniently at the reflux temperature of the solvent.

The compounds of formula (IV) may be prepared by reacting a compound offormula (V):

wherein A, Ar and R₁ are as defined in relation to the compound offormula (I), with a compound of formula (VI):

H₂N—CO—Z₁—L₂  (VI)

wherein Z₁ is as defined in relation to the compound of formula (IV) andL₂ represents a leaving group.

The reaction between the compounds of formulae (V) and (VI) is carriedout in an aprotic solvent, such as acetonitrile, at a temperature whichprovides a suitable rate of formation of the required product, generallyat an elevated temperature and conveniently at the reflux temperature ofthe solvent; preferably the reaction is carried out in the presence ofbase, usually an organic base such as a trialkylamine, for exampletriethylamine or a complex such as potassium fluoride on celite (TakashiAndo, Junko Yamawaki, Chemistry Letters, 1979, p.45).

A preferred leaving group L₂ is a halogen atom, such as a chlorine atom.

The compounds of formula (V) are known, commercially availablecompounds.

The compounds of formula (VI) are known compounds or they are preparedusing methods analogous to those used to prepare known, commerciallyavailable compounds.

In a further aspect the invention provides a process for the preparationof a compound of formula (I), which process comprises demethylating acompound of formula (VII):

wherein A, Ar, R₂, R₃, R₄ X and Z are as defined in relation to thecompounds of formula (I); and thereafter, as required, converting any—NH— moiety so formed into a group NR, wherein R represents C₂₋₆ alkyl,an alkenyl or a cycloalkyl group.

The demethylation of the compounds of formula (VII) may be affected byusing any conventional demethylation process, for example by use ofmethods disclosed in J. Org. Chem., 1975, 40, 1850, ibid, 1984, 49, 2081or those methods disclosed in Synthesis 1991, 318.

The conversion of any —NH— moiety into a group NR5 wherein R5 representsa C₂₋₆ alkyl, an alkenyl or a cycloalkyl group may be carried out usingconventional alkylation, alkenylation or cycloalkylation methods, by useof the appropriate alkylhalide, alkenylhalide or cycloalkylhalide,suitably an iodide, in the presence of a base such as potassiumbicarbonate in an aprotic solvate such as tetrahrydrofuran.

In a further aspect the invention provides a compound of formula (VII)or a salt thereof or a solvate thereof as an intermediate.

A compound of formula (I), or a salt thereof, or a solvate thereof, mayalso be prepared by reacting a compound of formula (VIII):

wherein R₂, R₃ R₄ X and Z are as defined in relation to formula (I) andL₃ is a leaving group, such as a halogen, with a compound of formula(IX):

wherein A, Ar, R₁ are as defined in relation to formula (I); andthereafter, if required, carrying out one or more of the followingoptional steps:

(i) converting a compound of formula (I) into a further compound offormula (I);

(ii) preparing a salt of the compound of formula (I) and/or apharmaceutically acceptable solvate thereof.

The reaction between the compounds of formulae (VIII) and (IX) may becarried out in any suitable inert solvent, such as dichloromethane, inthe presence of a base, usually an organic base, for exampletriethylamine, at a temperature which provides a suitable rate offormation of the required product, generally at an elevated temperature,such as the reflux temperature of the solvent.

A suitable value for L₃ is chlorine.

A compound of formula (VIII) may be prepared by reaction between acompound of above defined formula (III) and a compound of formula (X):

H₂N—Z—L₃  (X)

wherein Z is as defined in relation to formula (I) and L₃ is as definedin relation to formula (VII).

The reaction between the compounds of formulae (III) and (X) may becarried under conventional acylation conditions for example in an inertsolvent, such as dichloromethane, in the presence of a base, usually anorganic base, for example triethylamine, at a temperature which providesa suitable rate of formation of the required product, generally at a lowto ambient temperature, preferably at ambient temperature.

The compounds of formula (X) are known, commercially availablecompounds.

A suitable conversion of one compound of formula (I) into a furthercompound of formula (I) involves the interconversion of variable R₁ inthe compounds of formula (I), for example the conversation of compoundswherein R₁ is H into compounds of formula (I) wherein R₁ representsalkyl, suitably C₂₋₆ alkyl, alkenyl or cycloalkyl or the above mentionedconversation of compounds wherein R₁ is methyl into compounds wherein R₁is hydrogen, C₂₋₆ alkyl, alkenyl or cycloalkyl.

It will be appreciated that in any of the abovementioned reactions andconversions any reactive group in the substrate molecule may beprotected, according to conventional chemical practice. The methods offormation and removal of such protecting groups are those conventionalmethods appropriate to the molecule being protected.

As mentioned above the compounds of the invention are indicated ashaving useful therapeutic properties: The present invention accordinglyprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof and/or a pharmaceutically acceptable solvate thereof, foruse as an active therapeutic substance.

More particularly, the present invention provides a compound of formula(I), or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof, for use in the treatment ofand/or prophylaxis of arrhythmia, especially cardiac arrhythmia such asventricular arrhythmia, and also ischaemic rhythm disorders.

A compound of formula (I), or a pharmaceutically acceptable salt thereofand/or a pharmaceutically acceptable solvate thereof, may beadministered per se or, preferably, as a pharmaceutical composition alsocomprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceuticalcomposition comprising a compound of the general formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, and a pharmaceutically acceptable carriertherefor.

A compound of formula (I) or a pharmaceutically acceptable salt thereofand/or a pharmaceutically acceptable solvate thereof is normallyadministered in unit dosage form.

An amount effective to treat the disorder hereinbefore described dependsupon such factors as the efficacy of a compound of formula (I), theparticular nature of the pharmaceutically acceptable salt orpharmaceutically acceptable solvate chosen, the nature and severity ofthe disorders being treated and the weight of the mammal. However, aunit dose will normally contain 0.1 to 500 mg for example 2 to 50 mg, ofthe compound of the invention. Unit doses will normally be administeredonce or more than once a day, for example 2,3,4,5 or 6 times a day, moreusually 2 to 4 times a day, such that the total daily dose is normallyin the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 1 to1000 mg, for example 1 to 200 mg, that is in the range of approximately0.02 to 3 mg/kg/day, more usually 0.1 to 3 mg/kg/day, for example 0.15to 2 mg/kg/day.

At the above described dosage range, no toxicological effects areindicated for the compounds of the invention.

In such treatment, the compound may be administered by any suitableroute, e.g. by the oral, parenteral or topical routes. For such use, thecompound will normally be employed in the form of a pharmaceuticalcomposition in association with a human or veterinary pharmaceuticalcarrier, diluent and/or excipient, although the exact form of thecomposition will naturally depend on the mode of administration.

Compositions are prepared by admixture and are suitably adapted fororal, parenteral or topical administration, and as such may be in theform of tablets, capsules, oral liquid preparations, powders, granules,lozenges, pastilles, reconstitutable powders, injectable and infusablesolutions or suspensions, suppositories and transdermal devices. Orallyadministrable compositions are preferred, in particular shaped oralcompositions, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

Solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the active compound in a vehicle and filtersterilising before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the active compound is suspended in the vehicle instead ofbeing dissolved and sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the active compound.

For topical administration, the composition may be in the form of atransdermal ointment or patch for systemic delivery of the compound andmay be prepared in a conventional manner, for example, as described inthe standard textbooks such as ‘Dermatological Formulations’—B. W. Barry(Drugs and the Pharmaceutical Sciences—Dekker) or Harrys Cosmeticology(Leonard Hill Books).

In addition such compositions may contain further active agents such asanti-hypertensive agents and diuretics.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

As used herein the term ‘pharmaceutically acceptable’ embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term ‘pharmaceutically acceptable salt’ embraces aveterinarily acceptable salt.

The present invention further provides a method for the treatment and/orprophylaxis of arrhythmia, especially cardiac arrhythmia such asventricular arrhythmia, and also ischemic rhythm disorders in a human ornon-human mammal which comprises administering an effective, non-toxic,amount of a compound of the general formula (I), or a pharmaceuticallyacceptable salt thereof and/or a pharmaceutically acceptable solvatethereof to a human or non-human marital in need thereof.

Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

In the treatment and/or prophylaxis of arrhythmia and/or ischaemicarrhythmia disorders the compound of the general formula (I), or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, may be taken in doses, such as thosedescribed above.

Similar dosage regimens are suitable for the treatment and/orprophylaxis of non-human mammals.

In a further aspect the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof, for the manufacture of amedicament for the treatment of arrhythmia, especially cardiacarrhythmia such as ventricular arrhythmia, and also ischaemic rhythmdisorders.

No toxicological effects are indicated when a compound of formula (I) ora pharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof is administered in the above mentioned dosageranges.

The following Descriptions and Examples illustrate the invention but donot limit it in any way.

DESCRIPTION 1 3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]propanamide

6.42 g (60 mmol) 3-Chloropropanamide, 5.85 g (30 mmol)N-methyl-3,4-dimethoxybenzeneethanamine and 7.7 g (75 mmol)triethylamine in 100 ml acetonitrile were stirred under reflux for 18hours. The reaction mixture was concentrated in vacuo and the residuepurified by chromatography on silicagel using methylenechloride/methanol: 92/8 to yield 5.12 g (64.1%) of the desired compoundas an orange oil.

¹H NMR (CDCl₃) δ=2.40 (s, 3H, NCH₃); 2.46 (t, 25H, J=5.9 Hz, CH₂);2.74-2.79 (m, 6H, 3CH₂); 3.85 and 3.87 (2s, 6H, 2CH₃O); 6.70-6.78 (m,3H, 3Ar); 7.71 (broad band, 2H, exch D₂O, NH₂) ppm.

DESCRIPTION 2N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-1,3-propanediamine

1.5 g (5.6 mmol)3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]propanamide (D1) in drytetrahydrofuran were added dropwise to a suspension of 0.64 g (1.7 mmol)lithium aluminium hydride in 20 ml dry diethylether whilst stirring. Themixture was heated under reflux for 2 hours then cooled with a bath ofice water before carefully adding dropwise 0.65 ml water, 0.65 ml 15%aqueous NaOH, then 1.95 ml water. The mixture was dried over MgSO₄,concentrated in vacuo and the residue was purified twice bychromatography on basic alumina using methylene chloride/methanol: 95/5then methylene chloride/methanol/30% aqueous ammonia: 90/10/0.1 to yield0.86 g (60.8%) of the desired compound.

¹H NMR (CDCl₃) δ=1.65 (m, 2H, CH₂); 2.15 (broad band, 2H, exch D₂O,NH₂); 2.30 (s, 3H, NCH₃); 2.47 (t, 2H, J′=7.4 Hz, CH₂); 2.53-2.79 (m,6H, 3CH₂); 3.85 an (2s, 6H, 2CH₃O); 6.71-6.82 (m, 3H, 3Ar) ppm.

DESCRIPTION 3 N-(3-Chloropropyl)-4-nitrobenzamide

A solution of 6.43 g (49 mmol) 3chloropropylamine and 13.6 ml (98 mmol)triethylamine in 220 ml methylene chloride was cooled by an ice bath and9 g (48.5 mmol) 4-nitrobenzoyl chloride were added fractionwise. Afterone hour stirring at room temperature the organic phase was washed twicewith water, dried over MgSO₄ and concentrated in vacuo to afford 10.68 g(91%) of beige crystals. ¹H NMR was consistent with the desiredstructure.

EXAMPLE 1N-[3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]propyl]-4-nitrobenzamideHydrochloride

800 mg (3.17 mmol)N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-1,3-propanediamine (D2), 630mg (3.33 mmol) 4-nitro benzoyl chloride and 0.35 g (3.49 mmol)triethylamine in 30 ml methylene chloride were stirred for 2 hours atroom temperature. The mixture was washed with water, dried over MgSO₄and concentrated in vacuo. The residue was purified twice bychromatography on silicagel using methylene chloride/methanol: 97/3 then94/6 yielding 700 mg (55%) of the desired compound as a base. Thecompound was salified in methylene chloride by adding a solution ofhydrochoric acid in diethyl ether yielding 594 mg (43%) of the desiredcompound as a yellow solid: mp =80-90° C.

¹H NMR (DMSO-d₆) δ=2.00 (m, 2H, CH₂); 2.79 (s, 3H, NCH₃); 2.90 (m, 2H,CH₂); 2.95 (m, 2H, CH₂); 3.20 (m, 2H, CH₂); 3.35 (m, 2H, CH₂); 3.72 and3.74 (2s, 6H, 2CH₃O); 6.80-6.96 (m, 3H, Ar); 8.12 (d, 2H, J=7.9 Hz, Ar);8.33 (d, 2H, J=7.9 Hz, Ar); 9.05 (broad band, 1H, exch D₂O, NH); 10.45(broad band, 1H, exch D₂O, NH) ppm.

EXAMPLE 2 N-[3-[[2-(3,4-Dimethoxyphenyl)ethyl]amino]propyl]-4-nitroBenzamide Hydrochloride

A solution of 10.62 g (44 mmol) N-(3-chloropropyl)-4nitrobenzamide (D3),8.1 g (45 mmol) homoveratrylamine and 6.26 ml triethylamine in 200 mlmethylene chloride was refluxed for 48h. The solvent was thenconcentrated in vacuo and the residue dissolved in water. The aqueousphase was first washed with methylene chloride, then made basic withaqueous NaOH and finally extracted twice with methylene chloride. Thissecond organic phase was dried over MgSO₄ and concentrated in vacuoaffording 12 g of a crude residue. This residue was purified bychromatography on silicagel using CH₂Cl₂/MeOH/NH₄OH: 85/10/5 to afford4.4 g of the title compound as an yellow oil (free base).

This compound was dissolved in methanol and acidified by a solution ofanhydrous hydrogen chloride in diethyl ether, affording after drying 4.4g of the title compound as light beige crystals. mp.: 141-2° C. ¹H NMR(DMSO-d6) δ=1.93 (m, 2H, CH₂); 2.89-3.16 (m, 6H, 3×CH₂); 3.40 (m, 2H,CH₂); 3.72 and 3.75 (2s, 6H, 2×OCH₃); 6.74-6.91 (m, 3H, Ar); 8.12 (d,2H, J=8.6 Hz, Ar); 8.32 (d, 2H, J=8.6 Hz, Ar); 9.12 (broad band, 2H,exch. D₂O, NH₂+); 9.15 (t, 1H, exch. D₂O, NH) ppm.

Pharmacological Data Methodology

Guinea pigs (300-350 g) were anesthetized by intravenous injection ofsodium pentobarbital (60 mg/Kg). After thoracotomy the heart was rapidlyexcised and placed in oxygenated Tyrode solution. Papillary muscles wereremoved from the right ventricle. Preparations were then fixed to thesilastic base of a 5 ml organ bath and superfused with oxygenated Tyrodesolution maintained at 37±° C.

The modified Tyrode solution (pH 7.35) contained the following (mM):NaCl 125, KCl 4.0, MgCl₂0.5, CaCl₂1.8, NaHCO₃24, NaH₂PO₄0.9 and glucose5.5. The solution was equilibrated with a gas mixture of 95% O₂-5% CO₂.

After a stabilisation period (at least 1h), transmembrane actionpotentials were recorded with conventional microelectrodes (10 MOhm)connected to a high input impedance amplifier (BIOLOGIC VF 180).External stimuli were delivered to the preparation with bipolar platinumelectrodes placed at one end of the muscle. The pulse duration was 1 msand the amplitude was twice threshold. The basic cycle length was 1000ms (PULSAR 6i stimulator). The signals were monitored on a storageoscilloscope (GOULD 1602) and simultaneously recorded on a digital taperecorder (BIOLOGIC DTR 1200) for further analysis.

Measurements were made of action potential amplitude (APA) and actionpotential durations at 30 and 90% repolarization (APD30 and APD90respectively). Recordings were made after 30 min of equilibration foreach concentration. Only recordings in which the same impalement wasmaintained throughout the entire experiment were used for analysis.

What is claimed is:
 1. A compound of formula (I):

or a salt thereof, or a solvate thereof, characterised in that: Arrepresents substituted or unsubstituted aryl, wherein the optionalsubstituents are selected from alkyl, hydroxy or alkoxy or, if attachedto adjacent carbon atoms any two substituents together with the carbonatoms to which they are attached may form a fused heterocyclic ring offive to six atoms wherein one, two or three of the said atoms are oxygenor nitrogen; A represents a C₁₋₄ n-alkylene group wherein each carbon isoptionally substituted by 1 or 2 C₁₋₆ alkyl groups; R₁ representshydrogen, alkyl, alkenyl or cycloalkyl; one or two of of the group ofR₂, R₃ and R₄ represents nitro the remaining members of the group of R₂,R₃ and R₄ represent hydrogen; X represents a —CO—NH— moiety; and Zrepresents C₂₋₄ n-alkylene group wherein each carbon is optionallysubstituted by 1 or 2 C₁₋₆ alkyl groups.
 2. A compound according toclaim 1, wherein Ar represents a substituted or unsubstituted phenylgroup.
 3. A compound according to claim 1, wherein Ar represents aphenyl group substituted with 1 or 2 alkoxy groups.
 4. A compoundaccording to claim 1, wherein R₁ represents hydrogen, C₂₋₆ alkyl,alkenyl or cycloalkyl.
 5. A compound according to claim 1, wherein R₁ ishydrogen.
 6. A compound according to claim 1, wherein one of R₂, R₃ andR₄ represents nitro and the remaining members of the group of R₂, R₃ andR₄ represent hydrogen.
 7. A compound according to claim 6, wherein R₂represents 4-nitro and R₃ and R₄ each represents hydrogen.
 8. A compoundaccording to claim 1, wherein Z represents CH₂CH₂CH₂.
 9. A compoundwhich is N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride.
 10. A process for preparing a compound offormula (I) as defined in claim 1, or a salt thereof, or a solvatethereof, which process comprises: (i) reacting a compound of formula(II):

 wherein A, Ar, R₁ and Z are as defined in relation to formula (I), witha compound of formula (III):

 wherein R₂, R₃ and R₄ are as defined in relation to formula (I) and L₁represents a leaving group; or (ii) demethylating a compound of formula(VII):

 wherein A, Ar, R₂, R₃, R₄, X and Z are as defined in relation to thecompounds of formula (I); and thereafter, as required, converting any—NH— moiety so formed into a group NR₅ wherein R₅ represents C₂₋₆ alkyl,an alkenyl or a cycloalkyl group; or (iii) reacting a compound offormula (VIII):

 wherein R₂, R₃ R₄ X and Z are as defined in relation to formula (I) andL₃ is a leaving group, such as a halogen, with a compound of formula(IX):

 wherein A, Ar, R₁ are as defined in relation to formula (I); andthereafter carrying out one or more of the following optional steps: (i)converting a compound of formula (I) into a further compound of formula(I); (ii) preparing a salt of the compound of formula (I) and/or apharmaceutically acceptable solvate thereof.
 11. A pharmaceuticalcomposition comprising a compound of formula (I), as defined in claim 1,or a pharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, and a pharmaceutically acceptable carrier.12. A method for the treatment and/or prophylaxis of arrhythmia andischaemic rhythm disorders in a human or non-human mammal whichcomprises administering an effective, non-toxic amount of a compound ofthe general formula (I) as defined in claim 1, or a pharmaceuticallyacceptable salt thereof and/or a pharmaceutically acceptable solvatethereof to a human or non-human manual in need thereof.
 13. A compoundwhich is N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-4-nitrobenzamide; or a salt thereof, or a solvate thereof.
 14. The compoundaccording to claim 13 which isN-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-4-nitrobenzamide hydrochloride.